Neurotrophins are required for nerve growth during development

Although the requirement of neurotrophins for the prevention of cell death in the peripheral nervous system is well established, their physiological involvement in nerve growth is still unclear. To address this question, we generated a mouse that expresses the green fluorescent protein in post-mitotic neurons, allowing the repeated visualization of all motor and sensory axons during development. We imaged the growth of these axons into the limb bud of day 10.5 embryos. Sensory axons, but rarely motor axons, were targeted to ectopically placed beads containing any of the neurotrophins NGF, BDNF, NT-3 or NT-4/5. Conversely, a combination of function-blocking monoclonal antibodies to NGF, BDNF and NT-3 dramatically inhibited elongation of both sensory and motor axons in the limb bud, indicating that the growth of mixed nerves is dependent upon neurotrophins during development

γ-Secretase-Regulated Mechanisms Similar to Notch Signaling May Play a Role in Signaling Events, Including APP Signaling, Which Leads to Alzheimer’s Disease

Although gamma-secretase was first identified as a protease that cleaves amyloid precursor protein (APP) within the transmembrane domain, thus producing A beta peptides that are thought to be pathogenic in Alzheimer\u27s disease (AD), its physiological functions have not been fully elucidated. In the canonical Notch signaling pathway, intramembrane cleavage by gamma-secretase serves to release an intracellular domain of Notch that shows activity in the nucleus through binding to transcription factors. Many type 1 transmembrane proteins, including Notch, Delta, and APP, have recently been shown to be substrates for gamma-secretase, and their intracellular domains are released from the cell membrane following cleavage by gamma-secretase. The common enzyme gamma-secretase modulates proteolysis and the turnover of possible signaling molecules, which has led to the attractive hypothesis that mechanisms similar to Notch signaling contribute widely to proteolysis-regulated signaling pathways. APP is also likely to have a signaling mechanism, although the physiological functions of APP have not been elucidated. Indeed, we have shown that the intracellular domain of APP alters gene expression and induces neuron-specific apoptosis. These results suggest that APP signaling responds to the onset of AD. Here, we review the possibility of gamma-secretase-regulated signaling, including APP signaling, which leads to AD

Dynamic Nature of the p75 Neurotrophin Receptor in Response to Injury and Disease

Neurotrophins and their respective tropomyosin related kinase (Trk) receptors (TrkA, TrkB, and TrkC) and the p75 neurotrophin receptor (p75(NTR)) play a fundamental role in the development and maintenance of the nervous system making them important targets for treatment of neurodegenerative diseases. Whereas Trk receptors are directly activated by specific neurotrophins, the p75(NTR) is a multifunctional receptor that exerts its effects via heterodimeric interactions with TrkA, TrkB, TrkC, sortilin or the Nogo receptor to regulate a wide array of cellular functions. By partnering with different receptors the p75(NTR) regulates binding of mature versus pro-neurotrophins and activation of different signaling pathways with outcomes ranging from growth and survival to cell death. While the developmental downregulation of the p75(NTR) has raised questions regarding its role in the mature nervous system, recent data have revealed widespread expression of low levels, a role in synaptic plasticity and adult neurogenesis and upregulation in response to injury or disease. Studies are needed to better understand these processes, particularly in the damaged nervous system, but will be complicated by expression of p75(NTR) on immune cells including macrophages and microglia that are intimately involved in disease and repair processes. Recent approaches that regulate p75(NTR) function with small non-peptide ligands have demonstrated potent neuroprotection in models of injury and neurodegenerative diseases that highlight the importance of the p75(NTR) as a therapeutic target. Future studies hold the promise of revealing a wealth of information on the multifaceted actions of the p75(NTR) that will inform the design of new neurotrophin-based therapies